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Otis was born in Frederick, Maryland on March 25, 1838. He attended the University of Rochester, where he was a member of the (now defunct) Iota Chapter of St. Anthony Hall aka the Fraternity of Delta Psi. He graduated from Harvard Law School in 1860 and was practising law during the first year of the Civil War.

During the American Civil War, Otis was appointed captain in the 140th New York Regiment. He fought at the battles of Fredericksburg, Chancellorsville and Gettysburg. On December 23, 1863 he was promoted to lieutenant colonel of his regiment. At the Battle of Spotsylvania the regiment's colonel was killed and Otis assumed command. He fought in all the battles of the Overland Campaign. During the Siege of Petersburg, he assumed command of the 1st Brigade, 2nd Division in V Corps leading it into action at the Battle of Peebles' Farm. During this battle he was severely wounded effectively ended his field career during the Civil War. He was promoted to brevetbrigadier general of volunteers for actions at Peebles' Farm. Otis eventually recovered and was appointed lieutenant colonel of the 22nd U.S. Infantry in 1867.

Otis continued serving in the army during the Indian Wars as part of the 22nd U.S. including campaigning in Montana in the aftermath of the Battle of the Little Bighorn. On February 8, 1880 he was appointed colonel of the 20th U.S. Infantry. On November 28, 1893, he was appointed brigadier general in the regular army. He later commanded the Department of the Columbia and the Department of Colorado.

On May 4, 1898, he was appointed major general of volunteers and was sent to the Philippines with reinforcements for General Wesley Merritt. Otis assumed command of the Eighth Army Corps, replacing Merritt, who had become the military governor of the Philippines. Merritt served as military governor only briefly before he returned to the United States. On August 28, 1898 Otis was appointed Military Governor for the Philippines.

He also continued in command of Eighth Corps during the Philippine–American War. He conducted the U.S. Army during the Battle of Manila in 1899 and during the first phase of the insurrection before fighting turned primarily to guerrilla warfare.

Otis's response when Emilio Aguinaldo tried to stop the war by sending an emissary to General Otis to appeal for an end to the fighting in the Second Battle of Manila was, "fighting, having begun, must go on to the grim end."[2]

Otis also oversaw many of the first atrocities of the Philippine–American War by American soldiers:

The conduct of the Washington Volunteers has been the subject of special investigations for some time. They deny wanton burning or cruelties. And still there are strong indications that they practised these infractions to some extent.[3]

Otis was a skilled general and able administrator. However, he was generally disliked by his subordinates and peers and received harsh treatment in the press. He was known as "Granny" by his troops because of his age and graying hair.[4]:27–29 On the other hand, Rudolph Rau writes of Otis' work in the Philippines that "He delegated no authority, was pompous and fuzzy, and inspired few".[5] He died in Rochester, New York on October 21, 1909 from painful angina.